This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Over 90% of new HIV-1 infections occur as the result of unprotected sex, and women are biologically more vulnerable to HIV-1 infection. Because of gender inequality, particularly in developing countries, condoms (while effective at preventing HIV-1 infection when used consistently and correctly) are simply not a feasible option for many women. The development of a prevention method that women themselves could control could save millions of lives. This project will test the feasibility and efficacy of new compounds that have been demonstrated to block HIV-1 infection in cell culture experiments, but our focus will be on chemicals that bind to tissues and thus create a coating that prevents attachment of the HIV virus to susceptible tissues such as the vagina. Over the course of 3 years, we will apply these new compounds to the vagina of macaques singly and repeatedly to see if they prevent vaginal transmission of SIV and SHIV to macaques. Repeated exposures will be performed to ensure that these compounds are safe with continued use. It has been postulated that dendritic cells (DC) as well as Langerhans cells (LC) in the genital mucosa are the first cells to encounter HIV-1. In rhesus monkeys LC and resident DC located in the genital mucosa have been shown to be the dominant cell type infected following non-traumatic intravaginal exposure to SIV. Since we and others have shown that cell-free viral particles ineffectively cross genital epithelial cells, it is likely that HIV-1 hijacks host cells as "Trojan horses" to cross the normally impermeable genital epithelium in the absence of lesions. Our goal in this project is to develop compounds that prevent HIV-1 hijacking of LC and DC and to test them as microbicides in an in vivo vaginal transmission assay.